CN1066624C - Dry mix formulation for bisphosphonic acids - Google Patents

Dry mix formulation for bisphosphonic acids Download PDF

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Publication number
CN1066624C
CN1066624C CN93120408A CN93120408A CN1066624C CN 1066624 C CN1066624 C CN 1066624C CN 93120408 A CN93120408 A CN 93120408A CN 93120408 A CN93120408 A CN 93120408A CN 1066624 C CN1066624 C CN 1066624C
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phosphonic acids
amino
hydroxy
active component
propylidene
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CN1098907A (en
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S·R·贝查德
K·A·克雷默
A·V·卡达力
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Merck Sharp and Dohme LLC
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    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
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Abstract

Pharmaceutical compositions of bisphosphonic acids, and salts thereof, are prepared by direct compression/dry mix tablet formulation. These pharmaceutical compositions are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease.

Description

Two phosphonic dry mix formulations
It is one of the most general method that pharmaceuticals industry adopts the whole bag of tricks to come medicament, especially wet granulation in the mixing tab agent formulation.
Disclose multiple pair of phosphonic acids, they can be used for treating and preventing to relate to the disease of bone resorption, and representational example can be seen United States Patent (USP) No. 3962432; No. the 4054598th, United States Patent (USP); No. the 4267108th, United States Patent (USP); No. the 4327039th, United States Patent (USP); No. the 4621077th, United States Patent (USP); No. the 4624947th, United States Patent (USP); No. the 4746654th, United States Patent (USP); No. the 4922077th, United States Patent (USP); Disclose No. 0252504 with European patent.But the standard method of two phosphonic preparation tablets has run into serious difficulty.
The two phosphonic acids that particularly have nitrogenous basic functional group can interact with the lactose of standard preparation, thereby cause variable color, instability and render a service reduction.The degraded of this active component exist under water and/or the pyritous situation particularly evident.By inference, this incompatibility specifically is owing to Mei Lade (or " pale brown ") reaction, and wherein two phosphonic free amine group groups react with " glycosidic " oh group of sugar (for example lactose), finally form the degradation product of brown variable color.Although this problem can be avoided by not adding lactose, it is normally more satisfactory to make inert diluent with lactose.
The invention solves this problem, it has avoided this interaction between the bis phosphoric acid and lactose in the preparation by a kind of tablet formulation and method are provided.In addition, the present invention also provides the advantage of preparation, because it only needs composition to be mixed and do not need to granulate before tabletting or add water.
First aspect of the present invention relates to prepare by direct compacting (dry mixed) tablet formulation the method for two phosphonic Pharmaceutical compositions.This method adopts mixes two phosphonic acids and does not add water with minimum other processing aid.This tablet formulation is by mixing the preparation composition before direct compression and preparing without hydration (promptly other water not being added in this mixture).
More specifically, this aspect of the present invention relates to the preparation method of the tablet that contains two phosphonic acids active component, it comprises: with this active component and diluent, dry adhesives, disintegrating agent and can be selected from one or more following supplementary elements and mix: compression aids, correctives, flavour enhancer, sweeting agent and antiseptic, thus make mixture; With lubricator lubricated this mixture; And the lubricated mixture of the warp that will obtain is pressed into required tablet form.
The method of the disclosure can be used to prepare solid dosage forms, especially tablet hyoscine.
Preferable absorbent comprises lactose.Although can use aqueous high flow rate lactose, from the viewpoint of continued operation, especially preferred Lactis Anhydrous.
Preferred dry adhesives is a cellulose, especially preferably microcrystalline cellulose.Microcrystalline Cellulose can be buied from FMC Corp., merchant " Avicel " by name.
Disintegrating agent can be one of some modified starches or modified cellulose polymer, especially preferred crosslinked carmellose sodium (crosscarmellose sodium).Crosslinked carmellose sodium can " Ac-di-sol " trade name be buied.
Preferred lubricant comprises magnesium stearate.
The two phosphonic example that can be used as active component among the present invention comprises following compounds or its pharmaceutically acceptable salt: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-; N-methyl-4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-; 4-(N, N-dimethylamino)-1-hydroxy butylidene-1, the two phosphonic acids of 1-; 3-amino-1-hydroxy propylidene-1, the two phosphonic acids of 1-; 3-(N, N-dimethylamino)-1-hydroxy propylidene-1, the two phosphonic acids of 1-; 1-hydroxyl-3-(N-methyl-N-amyl group amino) propylidene-1, the two phosphonic acids of 1-; 1-hydroxyl-2-[3-pyridine radicals] ethylidene-1, the two phosphonic acids of 1-; And 4-(hydroxyl methylene-1, the two phosphonic acids of 1-) piperidines.
Two phosphonic preparation methoies can be referring to No. the 3962432nd, United States Patent (USP) for example; No. the 4054598th, United States Patent (USP); No. the 4267108th, United States Patent (USP); No. the 4327039th, United States Patent (USP); No. the 4407761st, United States Patent (USP); No. 4621077, United States Patent (USP); No. the 4624947th, United States Patent (USP); No. the 4746654th, United States Patent (USP); No. the 4922077th, United States Patent (USP) and European patent disclose No. 0252504.Specifically, 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-and 4-amino-1-hydroxy butylidene-1, the preparation method of the two phosphonic acids list sodium salt trihydrates of 1-can be respectively referring to No. the 4922077th, No. the 4407761st, United States Patent (USP) and United States Patent (USP).
Two phosphonic pharmaceutically acceptable salts also can be with in the present invention.Two phosphonic alkali salt examples comprise ammonium salt, alkali metal salt such as potassium salt and sodium salt (comprising a sodium salt, disodium salt and trisodium salt) (these salt are preferred), alkali salt such as calcium salt and magnesium salt, salt such as hexanamine salt with organic base formation, the N-methyl-D-glucamine salt and with amino acids formed salt such as arginine salt, lysinate etc.Preferred nontoxic and physiologically acceptable salt.These salt can prepare with method well known in the art.For example referring to No. the 4922077th, United States Patent (USP).
Preferred in the present invention two phosphonic acids are 4-amino-1-hydroxy butylidenes-1, the two phosphonic acids of 1-.Particularly preferred pair of phosphonic acids is 4-amino-1-hydroxy butylidene-1,1-two phosphonic sodium salt, especially 4-amino-1-hydroxy butylidenes-1, the two phosphonic acids list sodium salt trihydrates of 1-.
Another aspect of the present invention is containing of directly compacting of two phosphonic Pharmaceutical compositions tablets for example, and it is prepared by the method for the disclosure.By weight, these Pharmaceutical compositions generally contain the processing aid that the two phosphonic acids active component of the 0.5-40% that has an appointment and about 60-99.5% do not add water.More particularly, processing aid is diluent, dry adhesives, disintegrating agent and lubricant.Preferred processing aid comprises Lactis Anhydrous or moisture high flow rate lactose, microcrystalline Cellulose, crosslinked carmellose sodium and magnesium stearate.
Preferred Pharmaceutical composition by weight, comprises the two phosphonic acids active component of about 0.5-40%, about 10-80% Lactis Anhydrous or moisture high flow rate lactose, about 5-50% microcrystalline Cellulose, the crosslinked carmellose sodium of about 0.5-10% and about 0.1-5% magnesium stearate.
Preferred Pharmaceutical composition is generally tablet form.This tablet can be net weight 50mg to 1g for example; More preferably net weight is the tablet of 100-500mg, and the tablet that with the net weight is 200-300mg is best.
Preferred Pharmaceutical composition of the present invention by weight, contains the two phosphonic acids of the 0.5-25% that has an appointment, and described pair of phosphonic acids is selected from 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-and 4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-; About 30-70% Lactis Anhydrous or moisture high flow rate lactose; About 30-50% microcrystalline Cellulose; The crosslinked carmellose sodium of about 0.5-5%; With about 0.1-2% magnesium stearate.
Particularly preferred Pharmaceutical composition by weight, contains the 1-25% active component of having an appointment; About 40-60% Lactis Anhydrous; About 35-45% microcrystalline Cellulose; The crosslinked carmellose sodium of about 0.5-2%; With about 0.1-1% magnesium stearate.
The preferred Pharmaceutical composition of estimating to can be used for commercial development is as follows: the tire tablet of free acid of 2.5mg:
By weight, about 1.63%4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-; About 56.87% Lactis Anhydrous; About 40% microcrystalline Cellulose; About 1% crosslinked carmellose sodium; With about 0.5% magnesium stearate.The tire tablet of free acid of 5mg:
By weight, about 3.25%4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-; About 55.25% Lactis Anhydrous; About 40% microcrystalline Cellulose; About 1% crosslinked carmellose sodium; With about 0.5% magnesium stearate.The tire tablet of free acid of 25mg:
By weight, about 1.64%4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-; About 42.1% Lactis Anhydrous; About 40% microcrystalline Cellulose; About 1% crosslinked carmellose sodium; With about 0.5% magnesium stearate.The tire tablet of free acid of 50mg:
By weight, about 21.8%4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-; About 36.7% Lactis Anhydrous; About 40% microcrystalline Cellulose; About 1% crosslinked carmellose sodium; With about 0.5% magnesium stearate.
Medicinal tablets compositions of the present invention also can contain one or more additional preparation compositions, and they can be selected from known multiple excipient in the field of pharmaceutical preparations.The character required according to tablet can be selected multiple composition, and they can be independent or blended, and this depends on their known application in the preparation tablet composition.Such composition comprises diluent, compression aids, disintegrating agent, lubricant, binding agent, correctives, flavour enhancer, sweeting agent and antiseptic, but is not limited to these.
" tablet " speech is meant the pharmaceutical dosage formulation of compacting that comprises all shapes and size herein, coating or coating not.The material that can be used for coating comprises hydroxypropyl emthylcellulose, hydroxypropyl cellulose, titanium dioxide, Pulvis Talci, sweeting agent and coloring agent.
Pharmaceutical composition of the present invention can be used for treating or prophylactic treatment calcium or phosphate metabolism disorder and relevant disease.These diseases can be divided into two classes:
Calcium salt, mainly be unusual (dystopy) precipitation, histopathology sclerosis and ostealleosis of calcium phosphate.
2. can be of value to the condition that reduces bone resorption.The minimizing bone resorption should improve the balance between absorption and the formation, reduces the bone loss or causes the bone increase.Reduce incidence rate and/or growth that bone resorption can alleviate the pain relevant with molten bone injury and reduce those infringements.
These diseases comprise: osteoporosis (comprise by due to estrogen deficiency, immobilization and the glucocorticoid with senile), osteodystrophy, Paget, myositis ossificans, Bechterew, malignant hypercalcemia, metastatic bone disease, periodontal, cholelithiasis, nephrolithiasis, urolithiasis, urinary stone, arteriosclerosis, and joint is scorching, bursitis, neuritis and tetany.
Increase bone resorption and can cause high calcium on the pathology and phosphate concn in the blood plasma, this can the application of the invention Pharmaceutical composition and be eased.
The following example purpose is to illustrate the present invention but is also unrestricted to scope of the present invention or spirit.
Embodiment 1
4-amino-1-hydroxy butylidene-1, tire every per 400 active component of preparation method composition (single sodium salt trihydrate) 6.55mg 26.2g Lactis Anhydrous of tablet of the two phosphonic 5mg of 1-, the crosslinked carmellose sodium NFA of NF 110.45mg 441.8g microcrystalline Cellulose NF 80.0mg 320.0g magnesium stearate fine powder NF 1.00mg 4.0g type 2.00mg 8.0g
With active component (being equivalent to the every anhydrous free acid of 5mg) and 1/3 microcrystalline Cellulose NF and 1/2 Lactis Anhydrous NF in ribbon blender with 20 RPM premixings 5 minutes.Remaining 2/3 microcrystalline Cellulose NF and 1/2 Lactis Anhydrous NF are added in this premix, it was mixed 10 minutes in 20RPM.Crosslinked carmellose sodium is added in this blended powder and mixed 5 minutes in 20RPM.At last magnesium stearate is added in this mixture by 90 mesh sieves and in 20RPM remix 5 minutes.Mixture with this after lubricated is pressed into the tablet of 5mg active component.
Embodiment 2
The tire preparation method of tablet of 4-amino-1-hydroxy butylidene-1, the two phosphonic 2.mg of 1-
Every active component of composition (single sodium salt trihydrate) 3.26mg Lactis Anhydrous, the crosslinked carmellose sodium NFA of NF 113.74mg microcrystalline Cellulose NF 80.0mg magnesium stearate fine powder NF 1.00mg type 2.00mg
Method with embodiment 1 prepares tablet.
Embodiment 3
The tire preparation method of tablet of 4-amino-1-hydroxy butylidene-1, the two phosphonic 10.0mg of 1-.
Every active component of composition (single sodium salt trihydrate) 13.05mg Lactis Anhydrous, the crosslinked carmellose sodium NFA of NF 103.95mg microcrystalline Cellulose NF 80.0mg magnesium stearate fine powder NF 1.00mg type 2.00mg
Method with embodiment 1 prepares tablet.
Embodiment 4
The tire preparation method of tablet of 4-amino-1-hydroxy butylidene-1, the two phosphonic 40.0mg of 1-
Every active component of composition (single sodium salt trihydrate) 51.21mg Lactis Anhydrous, the crosslinked carmellose sodium NFA of NF 64.79mg microcrystalline Cellulose NF 80.0mg magnesium stearate fine powder NF 1.00mg type 2.00mg
Method with embodiment 1 prepares tablet.
Embodiment 5
The tire preparation method of tablet of 4-amino-1-hydroxy butylidene-1, the two phosphonic 25mg of 1-.Every per 400 active component of composition (single sodium salt trihydrate) 32.75mg 131.0g Lactis Anhydrous, the crosslinked carmellose sodium NFA of NF 84.25mg 337.0g microcrystalline Cellulose NF 80.0mg 320.0g magnesium stearate fine powder NF 1.00mg 4.0g type 2.00mg 8.0g
Method with embodiment 1 prepares tablet.
Embodiment 6
The tire preparation method of tablet of 4-amino-1-hydroxy butylidene-1, the two phosphonic 50mg of 1-.Every per 400 active component of composition (single sodium salt trihydrate) 65.5mg 163.75g Lactis Anhydrous, the crosslinked carmellose sodium NFA of NF 110.0mg 275.0g microcrystalline Cellulose NF 120.0mg 300.0g magnesium stearate fine powder NF 1.5mg 3.75g type 3.0mg 7.5g
Method with embodiment 1 prepares tablet.
Embodiment 7 stability studies
The tablet formulation (being equivalent to the every anhydrous free 4-amino of 5mg-1-hydroxy butylidene-1, the two phosphonic acids of 1-) that under different conditions, prepares active component with different excipient.According to the tablet that the method preparation of embodiment 1 is directly suppressed, prepare the tablet of wet granular according to following method.Under the condition of worn-out open pallets and in 40 ℃/75% (relative humidity) tablet is carried out stability study, the result is as follows:
1. with preparation wet granulation and that contain Lactis Anhydrous the tablet variable color appearred in 2 weeks.
2. with preparation wet granulation and that contain lactose hydrous the tablet variable color appearred in 4 weeks.
3. after 4 weeks the tablet variable color does not appear with the preparation of directly suppressing (dry mixed) formulation preparation.The mensuration of active component confirms: do not have loss of tiring or degraded in the identical time.The table I has shown the stability of formulation feature of the preparation of direct compacting with respect to wet granulation.
Table 1
3 months data of 5mg sample stability sampling
(Three-Month?Data?of?5mg?Probe?Stability?Lots)
The percent of measuring when (a) the direct compression condition begins
Open type dish HDPE/CRC bottle
40 ℃ 101.2% of cpd adduct MK-0217 adduct----99.8%----40 ℃/75%RH 102.9%----98.5%----
100.9%*----60 ℃ of 100.6%----101.3%--------102.1%----* repetition values that RT/90%RH 103.5%
(b). the percent of measuring when the wet granulation condition begins
Worn-out open pallets HDPE/CRC bottle
40 ℃ 99.7% of adduct of epd adduct MK-0217----97.0%----
100.0％** ----40℃/75％RH?84.1％?15.9％ 94.6％ 5.6％
60 ℃ of 92.6% micro-* * * 94.3% micro-* * * of 99.7%**----
94.6%** trace RT/90%RH 101.4%----100.4%----
It is detectable (～5%) that 99.4%----* * contains desiccant * * * trace expression adduct peak, but can't under experiment condition
Quantitatively.Cpd=4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-.The preparation method of the tablet of wet granulation
1) Lactis Anhydrous, alendronate sodium and microcrystalline Cellulose are mixed in suitably big or small blender.
2) mixture is crossed the #30 sieve, and then mixed a period of time.
3) this mixture of powders is granulated until bonding occurring with an amount of water.
4) agglomerate that will wet is crossed #5 sieve.
5) granule of wet screening is put force air drier in 40-50 ℃ of drying until loss on drying during at 105 ℃ less than 2%.
6) with the suitable sieve of dried particles.
7) granule with dry screen mixes with crosslinked carmellose sodium, mixes with magnesium stearate then.
8) the granule compressed tablets of usefulness labelling.
Although above-mentioned description has been set forth principle of the present invention and has been illustrated with embodiment, but be understood that, the inventive method comprises all interim changes as herein described, method and the agreement adjusting, improve, abridge or replenish, is included in the scope of following claim and its equipollent.

Claims (16)

1. the preparation method that contains the tablet that is selected from following active component or its pharmaceutically acceptable salt: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, N-methyl-4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 4-(N, N-dimethylamino)-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 3-amino-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 3-(N, the N-dimethylamino)-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-3-(N-methyl-N-amyl group amino) propylidene-1, the two phosphonic acids of 1-; 1-hydroxyl-2-[3-pyridine radicals] ethylidene-1, the two phosphonic acids of 1-, and 4-(hydroxyl methylene-1, the two phosphonic acids of 1-) piperidines; Described preparation method comprises: with active component and the diluent that is selected from Lactis Anhydrous and moisture high flow rate lactose, dry adhesives, disintegrating agent with optionally be selected from one or more following supplementary elements and mix: compression aids, correctives, flavour enhancer, sweeting agent and antiseptic, thereby make mixture, with lubricator lubricated this mixture, and the lubricated mixture of the warp that will obtain is pressed into required tablet form.
2. according to the process of claim 1 wherein, active component is 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-.
3. according to the process of claim 1 wherein, active component is 4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-.
4. according to the process of claim 1 wherein, dry adhesives is a microcrystalline Cellulose.
5. according to the process of claim 1 wherein, disintegrating agent is selected from modified starch, modified cellulose polymer and crosslinked carmellose sodium, or their mixture.
6. according to the process of claim 1 wherein, disintegrating agent is crosslinked carmellose sodium.
7. according to the process of claim 1 wherein, lubricant is a magnesium stearate.
8. contain the solid dosage forms that is selected from following active component or its pharmaceutically acceptable salt: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, N-methyl-4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 4-(N, N-dimethylamino)-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 3-amino-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 3-(N, the N-dimethylamino)-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-3-(N-methyl-N-amyl group amino) propylidene-1, the two phosphonic acids of 1-; 1-hydroxyl-2-[3-pyridine radicals] ethylidene-1, the two phosphonic acids of 1-, and 4-(hydroxyl methylene-1, the two phosphonic acids of 1-) piperidines; Wherein, this solid dosage forms prepares with the method for claim 13.
9. Pharmaceutical composition, by weight, it contains the excipient that 0.5-40% active component and 60-99.5% mainly comprise following material: Lactis Anhydrous or moisture high flow rate lactose, microcrystalline Cellulose, crosslinked carmellose sodium and magnesium stearate; Described active component is selected from following chemical compound or its pharmaceutically acceptable salt: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, N-methyl-4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 4-(N, N-dimethylamino)-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 3-amino-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 3-(N, the N-dimethylamino)-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-3-(N-methyl-N-amyl group amino) propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-2-[3-pyridine radicals] ethylidene-1, the two phosphonic acids of 1-, and 4-(hydroxyl methylene-1, the two phosphonic acids of 1-) piperidines.
10. Pharmaceutical composition, by weight, it contains the 0.5-40% active component, 10-80% Lactis Anhydrous or moisture high flow rate lactose, 5-50% microcrystalline Cellulose, crosslinked carmellose sodium of 0.5-10% and 0.1-5% magnesium stearate; Described active component is selected from following chemical compound or its pharmaceutically acceptable salt: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, N-methyl-4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 4-(N, N-dimethylamino)-1-hydroxy butylidene-1, the two phosphonic acids of 1-, 3-amino-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 3-(N, the N-dimethylamino)-1-hydroxy propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-3-(N-methyl-N-amyl group amino) propylidene-1, the two phosphonic acids of 1-, 1-hydroxyl-2-[3-pyridine radicals] ethylidene-1, the two phosphonic acids of 1-, and 4-(hydroxyl methylene-1, the two phosphonic acids of 1-) piperidines.
11. Pharmaceutical composition according to claim 10, by weight, it contains the active component of 0.5-25%, the Lactis Anhydrous of 30-70% or moisture high flow rate lactose, the microcrystalline Cellulose of 30-50%, the crosslinked carmellose sodium of 0.5-5% and the magnesium stearate of 0.1-2%.
12. according to the Pharmaceutical composition of claim 10, wherein, active component is 4-amino-1-hydroxy butylidene-1, the two phosphonic acids of 1-.
13. according to the Pharmaceutical composition of claim 10, wherein, active component is 4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-.
14. Pharmaceutical composition according to claim 13, by weight, it contains the active component of 1-25%: 4-amino-1-hydroxy butylidene-1, the two phosphonic acids list sodium salt trihydrates of 1-, the Lactis Anhydrous of 40-60%, the microcrystalline Cellulose of 35-45%, the crosslinked carmellose sodium of 0.5-2% and the magnesium stearate of 0.1-1%.
15. the tablet that makes by the Pharmaceutical composition of claim 13.
16. the tablet that makes by the Pharmaceutical composition of claim 10.
CN93120408A 1992-12-02 1993-12-01 Dry mix formulation for bisphosphonic acids Expired - Lifetime CN1066624C (en)

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CA2149052C (en) 2003-03-25
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CY2236B1 (en) 2003-07-04
UA46701C2 (en) 2002-06-17
SK73195A3 (en) 1995-12-06
CA2149052A1 (en) 1994-06-09
WO1994012200A1 (en) 1994-06-09
HU9501590D0 (en) 1995-08-28
EP0690719B1 (en) 2000-10-04
CN1160076C (en) 2004-08-04
JPH08506092A (en) 1996-07-02
NO952184L (en) 1995-06-01
DE69329533D1 (en) 2000-11-09
GR3034936T3 (en) 2001-02-28
PT690719E (en) 2001-02-28
SK282100B6 (en) 2001-11-06
CZ134695A3 (en) 1995-10-18
FI113839B (en) 2004-06-30
US6090410A (en) 2000-07-18
JP4267877B2 (en) 2009-05-27
US5882656A (en) 1999-03-16
RU2148405C1 (en) 2000-05-10
CZ289966B6 (en) 2002-05-15
HU220604B1 (en) 2002-03-28
KR100473750B1 (en) 2005-03-07
EP0690719A1 (en) 1996-01-10
FI952685A (en) 1995-06-01
CN1233468A (en) 1999-11-03
DE69329533T2 (en) 2001-05-31
AU5611594A (en) 1994-06-22
NO308986B3 (en) 2000-11-27
JP2003073277A (en) 2003-03-12
LV12715A (en) 2001-09-20
JP3365634B2 (en) 2003-01-14
IL107741A0 (en) 1994-02-27
BG62795B1 (en) 2000-08-31
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PL309245A1 (en) 1995-10-02
HK1009252A1 (en) 1999-05-28
KR100286063B1 (en) 2001-05-02
US5681590A (en) 1997-10-28
AU677264C (en) 2005-09-29
IL107741A (en) 1997-06-10
NO952184D0 (en) 1995-06-01
ZA938979B (en) 1994-08-03
RO113429B1 (en) 1998-07-30
TW422707B (en) 2001-02-21
US5358941A (en) 1994-10-25
FI952685A0 (en) 1995-06-01
BG99663A (en) 1996-02-28
EP0690719A4 (en) 1996-01-24
CZ290197B6 (en) 2002-06-12
ATE196736T1 (en) 2000-10-15
KR20030096426A (en) 2003-12-31
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LV12715B (en) 2001-12-20
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JP3854187B2 (en) 2006-12-06

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